Development of novobiocin analogues that manifest anti-proliferative activity against several cancer cell lines
Development of novobiocin analogues that manifest anti-proliferative activity against several cancer cell lines
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DOI：
10.1021/jo702191a
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发表时间：
2008-03-21
影响因子：
3.6
通讯作者：
Blagg, Brian S. J.
中科院分区：
文献类型：
--
作者：
Burlison, Joseph A.;Avila, Christopher;Blagg, Brian S. J.
最近的研究表明，DNA促旋酶抑制剂，新生霉素，结合到以前未识别的ATP结合位点位于C-末端的热休克蛋白90和诱导降解热休克蛋白90依赖性客户蛋白在类似于700 μ M。作为这些研究的结果，已经报道了香豆素家族抗生素的几种类似物，并且显示出增加的Hsp 90抑制活性;然而，单体物质在测试浓度下缺乏表现出针对癌细胞系的抗增殖活性的能力。为了开发对癌细胞系产生生长抑制活性的更有效的化合物，围绕天然产物的异戊二烯化苯甲酰胺侧链研究了结构-活性关系。从这些研究中获得的结果已经产生了第一个新生霉素类似物，其表现出对几种癌细胞系的抗增殖活性。
Recent studies have shown that the DNA gyrase inhibitor, novobiocin, binds to a previously unrecognized ATP-binding site located at the C-terminus of Hsp90 and induces degradation of Hsp90-dependent client proteins at similar to 700 mu M. As a result of these studies, several analogues of the coumarin family of antibiotics have been reported and shown to exhibit increased Hsp90 inhibitory activity; however, the monomeric species lacked the ability to manifest anti-proliferative activity against cancer cell lines at concentrations tested. In an effort to develop more efficacious compounds that produce growth inhibitory activity against cancer cell lines, structure-activity relationships; were investigated surrounding the prenylated benzamide side chain of the natural product. Results obtained from these studies have produced the first novobiocin analogues that manifest anti-proliferative activity against several cancer cell lines.